Polyamino acids and method for producing the same

ABSTRACT

The invention relates to polyamino acids, to a method for producing the same and to their use as catalysts for enantioselective epoxidation of α,β-unsaturated enons and α,β-unsaturated sulfones.

The invention relates to polyamino acids, to a method for productionthereof, and to the use thereof as catalysts for enantioselectiveepoxidation.

Chirally nonracemic epoxides are valuable building blocks for producingoptically active agents and materials (e.g. a) Bioorg. Med. Chem., 1999,7, 2145-2156; b) Tetrahedron Lett., 1999, 40, 5421-5424). The greatestattention has been devoted in the literature to the epoxidation methodof Julia and Colonna, who were able to show that enantiomer-anddiastereomer-enriched polyamino acids (PAA) are able in the presence ofaqueous hydrogen peroxide solution and NaOH solution, and of an aromaticor halogenated hydrocarbon as solvent, to catalyze the enantioselectiveepoxidation of α,β-unsaturated enones (Angew.; Chem., Int. Ed. Eng.,1980, 19, 929-930).

Various methods for producing polyamino acids have been described (e.g.Adcances in Protein Chemistry, 1958, 13, 243-492; Russ. Chem. Rev.,1965, 34, 329; Comprehensive Chemical Kinetics, 1976, 15, 583-637). Mostof the methods make use of the principle of random polymerization, inwhich the n-carboxy anhydrides (NCA) of the appropriate amino acids arereacted with an initiator (e.g. amines, water, alcohols and alkoholates)in an inert solvent (e.g. acetonitrile, dioxane, THF, benzene). Thisresults in a mixture of polyamino acids with various chain lengths, andthe main product is seen to be polyamino acid having the chain lengthcalculated from the molecular ratio between NCA and initiator. Thepolymerizations are usually carried out at room temperature. Examples ofpolymerizations of NCAs at elevated temperature are, by contrast, rare.Thus, for example, high molecular weight films and fibers have beenproduced by polymerization of L-alanine-NCA (without explicit additionof initiator) or by polymerization of L-leucine-NCA (atmospherichumidity as initiator) with in boiling benzene (DuPont, 1957, U.S. Pat.No. 2,789,973). The reaction times were stated to be 1-10 days. Ebert etal. have also described the production of very high molecular weightpolyamino acids in analogy thereto. In this case, for example,poly-L-leucine with an average molecular weight of 400 000 g/mol wasproduced by polymerization in benzene (70° C., no explicit addition ofinitiator), and was investigated for its properties in relation to theproduction of fibers and sheets (Progr. Colloid & Polymer Sci, 1976, 60,183-193).

A number of procedures also exist for producing the required N-carboxyanhydrides and are known from the literature (e.g. Rec. Trav. Chim.Pays-Bas, 1954, 73, 347).

However, only certain polyamino acids can be used as catalyst in theJulià-Colonna epoxidation, because the reaction rate which can beachieved, and the possible enantiomeric excess (ee) depend very greatlyon the polyamino acid used and the way in which it is produced (e.g.Bioorg. Med. Chem., 1999, 7, 2145-2156, Tetrahedron, 1984, 40,5207-5211; Chirality, 1997, 9, 198-202). In general, polyamino acidswith an average molecular weight of <15 000 g/mol are used. Thecatalytic activity of the polyamino acid also depends to a high degreeon the existing polyamino acid conformation which in turn is cruciallyinfluenced by the method of production (e.g. Bull. Chem. Soc. Jpn.,2000, 73, 2115-2121; J. Org. Chem., 1993, 58, 6247-6254, Org. Lett.,2001, 3,683-686; ibit 2001, 3, 3839-3842). The catalysts mostly usedcurrently in the Julià-Colonna epoxidation are D- or L-polyleucine.Other polyamino acids which have been successfully used are, forexample, D- and L-neopentylglycine (EP-A 1 006 127) or D- or L-alanine.

Julià found that it is possible to obtain by polymerizing alanine-NCAwith n-butylamine a polyamino acid which is able to catalyze theenantioselective epoxidation of enones (Angew., Chem., Int. Ed. Eng.,1980, 19, 929-930). The reaction was carried out at room temperature inacetonitrile and took place within 4 days. After filtration of thepolymer and washing with ether it was possible to employ the polymer inthe epoxidation. Several variations in this procedure were made by Juliàand Colonna (e.g. J. Chem. Soc., Perkin 1, 1982, 1317; Tetrahedron,1983, 39, 1635; Tetrahedron, 1984, 40, 5207-5211), but thepolymerizations carried out at room temperature required a very longreaction time. A further distinct disadvantage of the method of Juliàand Colonna was the difficult workup of the polymer. It was possible byusing an amino-functionalized polymer (polystyrene) as initiator toproduce similarly active polymers which were, however, easier to handle(J. Org. Chem., 1990, 55, 6047-6049). The polymerization took place inthis procedure in tetrahydrofuran at room temperature over 40 h. Anotherprocedure for producing polyamino acids (especially poly-L-leucine, pLL)was patented by Ajinomoto Co., Inc. (JP 74 38,995) and used by Flisak etal. in the synthesis of SK&F 104353 (J. Org. Chem., 1993, 58, 6247-6254). In this method, N-carboxy anhydride was polymerized in the solid stateat room temperature with atmospheric humidity (5-10 days). A very highpurity of the N-carboxy anhydride used is absolutely necessary for goodcatalytic activity of the material. The high purity of the producedN-carboxy anhydride is also crucial in the method of Bentley et al.(Chirality, 1997, 9, 198-202). The solvent described for thepolymerization in this case is also THF (room temperature, reaction time3 days).

Besides random polymerization, polyamino acids have also been preparedby elaborate, stepwise polymerization in a peptide synthesizer (usingprotective group techniques) (e.g. Bull. Chem. Soc. Jpn., 2000, 73,2115-2121; Tetrahedron Lett., 1998, 39, 9297-9300; WO-A-0194327).

In addition, polyamino acids for the Julià-Colonna epoxidation have beenproduced by polymerizing N-carboxy anhydrides with amino-substitutedpolyethylene glycols (e.g. WO-A-0194327). Long polymerization times arerequired in this case too (several days).

In order to compare the catalytic activity of different polyamino acidpreparations, in the literature a standard test system with a polyaminoacid as catalyst and trans-chalcome as precursor is used for thedevelopment and description of novel methods. The quality of thepolyamino acid preparation can be deduced from the reaction rate and theresulting enantiomeric excess (ee).

It is an object of the present invention to provide catalysts and amethod for producing the catalysts which do not have the aforementioneddisadvantages in the enantioselective epoxidation. Simple andreproducible production of the catalysts is particularly important. Ahigh activity, stability, space-time yields and selectivity of thecatalysts is also important.

It has now been found, surprisingly, that a suitable catalyst can beobtained by reacting amino acid N-carboxy anhydride (amino acid-NCA) inaromatic solvents at elevated temperature and in the presence of aninitiator.

It has additionally been found, surprisingly, that isolation of thecatalyst is considerably simplified when C₁-C₄ alcohol is added to thereaction mixture before the filtration.

The inventive production of the catalyst is explained below.

Production of the catalyst can be described by way of example by thefollowing reaction scheme.

The times for producing the catalyst can be reduced from days to a fewhours. It has particularly surprisingly been found that the catalystproduced in this way has a considerably higher catalytic activity thancatalyst preparations produced by previously published methods. Inaddition, the catalyst can be produced in this way in reproduciblequality.

The influence of the mode of production on the activity of the catalystwas demonstrated with the aid of the standard test reaction, thepolyamino acid-catalyzed epoxidation of trans-chalcone to epoxychalcone(three-phase condition; cf production examples).

Suitable aromatic solvents are unsubstituted, alkylated, halogenated andinitiated benzene derivatives. Those to be emphasized are benzene;nitrobenzene, alkylbenzenes such as toluene, o-, m-, p-xylene, cresol,tetrahydronaphthalene; halobenzenes such as chloro-and dichlorobenzene.Those to be particularly emphasized are benzene, toluene, nitrobenzeneand chlorobenzene. Toluene is to be very particularly emphasized. It ispossible where appropriate to use solvent mixtures.

Preference is given to aromatic solvents in which precursor andinitiator are soluble under the reaction conditions.

The known amino acid-NCAs can be used as starting material for producingthe catalyst. Particularly suitable are the amino acid-NCAs described inthe above literature for the Julià-Colonna epoxidation. Particularpreference is given to D- and L-leucine-NCA, D- and L-alanine-NCA and D-and L-neopentylglycine-NCA. D- or L-leucine-NCA is very particularlypreferred.

Production of the amino acid-NCAs is known and can take place in analogyto known methods.

The initial concentration of the amino acid-NCAs can be varied within awide range. In general, from 0.5 to 25% by mass, preferably 1 to 10% bymass and particularly preferably 1 to 5% by mass of amino acid-NCA areused in the reaction mixture.

Initiators which can be used are the known initiators. In particularmonohydric and polyhydric alcohols or salts thereof, and monofunctionaland polyfunctional amines, can be used. The following amines areparticularly suitable: 1,3-diaminopropane, CLAMPS, n-butylamine,amine-substituted PEG.

The molar ratio of amino acid-NCA to equivalent of initiator can bevaried within a wide range and is between 4:1 and 200:1. The ratio ispreferably between 4:1 and 100:1; particularly preferably between 4:1and 50:1, very particularly preferably between 10:1 and 40:1. The ratiovaries depending on the initiator used. The average chain length can beinfluenced for example by the initiator and the ratio of amino acid-NCAto initiator.

The reaction temperature can be varied within a wide range and isbetween 30° C. and the boiling point of the reaction mixture. Thereaction temperature is preferably between 50° C. and the boiling pointof the reaction mixture, particularly preferably between 80° C. and 110°C., very particularly preferably between 90° C. to 110° C. The reactiontemperature can be varied during the course of the reaction. In oneembodiment of the invention, the temperature is increased after thestart of the reaction. In an alternative embodiment, the initiator ismetered into the boiling solvent, and the reaction mixture is kept atthe boiling point throughout the reaction time.

The reaction pressure can be varied within a wide range and is between0.5 and 5 bar, preferably between 0.9 and 1.5 bar, particularlypreferably atmospheric pressure.

The catalyst can be isolated from the reaction mixture by customarylaboratory methods. Thus, removal by filtration or centrifugation ispossible. The catalyst obtained in this way can then be subjected tofurther purification and workup steps such as washing and drying. It isadvantageous to add a C₁-C₄ alcohol before the filtration orcentrifugation. Methanol and ethanol are particularly suitable as C₁-C₄alcohol. The amounts of added alcohol can be varied within a wide rangeand is between 0.1:1 and 10:1 (v/v). Preferred ranges are between 0.5:1and 2:1 (v/v) the ratio 1:1 by volume is particularly preferred.

The inventive use of the catalyst is epoxidation reactions is explainedbelow.

An epoxidation reaction means the conversion of a C—C double bond intoan oxirane. In particular, an epoxidation reaction means the conversionof α,β-unsaturated enones or α,β-unsaturated sulfones into thecorresponding epoxides.

It is possible to employ as α,β-unsaturated enones or α,β-unsaturatedsulfones the compounds of the general formula (II)

in which

-   -   X is (C═O) or (SO₂), and    -   R⁵ and R⁶ are identical or different and are (C₁-C₁₈)-alkyl,        (C₂-C₁₈)-alkenyl, (C₂-C₁₈)-alkynyl, (C₃-C₈)-cycloalkyl,        (C₆-C₁₈)-aryl, (C₇-C₁₉)-aralkyl, (C₁-C₁₈)-heteroaryl or        (C₂-C₁₉)-heteroaralkyl,        -   where the radicals mentioned for R⁵ and R⁶ may be            substituted once or more than once by identical or different            radicals R⁷, halogen, NO₂, NR⁷R⁸, PO₀₋₃R⁷R⁸, SO₀₋₃R⁷, OR⁷,            CO₂R⁷, CONHR⁷ or COR⁷, and optionally one or more CH₂ groups            in the radicals R⁵ and R⁶ are substituted by O, SO₀₋₂, NR⁷            or PO₀₋₂R⁷,        -   where R⁷ and R⁸ are identical or different and are H,            (C₁-C₁₈)-alkyl, (C₂-C₁₈)-alkenyl, (C₂-C₁₈)-alkynyl,            (C₃-C₈)-cycloalkyl, (C₆-C₁₈)-aryl, (C₁-C₁₈)-heteroaryl,            (C₁-C₈)-alkyl-(C₆-C₈)-aryl,            (C₁-C₈)-alkyl-(C₁-C₁₉-heteroaryl,            (C₁-C₈)-alkyl-(C₃-C₈)-cycloalkyl radicals R⁷ and R⁸ may be            substituted once or more than once by identical or different            halogen radicals.

A (C₁-C₁₈)-alkyl radical means for the purposes of the invention aradical having 1 to 18 saturated C atoms and possibly having branches atany positions. It is possible to include in this group in particular theradicals methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl and hexyl.

A (C₂-C₁₈)-alkenyl radical has the features mentioned for. the(C₁-C₁₈)-alkyl radical, but at least one double bond must be presentwithin the radical.

A (C₂-C₁₈)-alkynyl radical has the features mentioned for the(C₁-C₁₈)-alkyl radical, but at least one triple bond must be presentwithin the radical.

A (C₃-C₈)-cycloalkyl radical means a cyclic alkyl radical having 3 to 8C atoms and optionally a branch in any position. Radicals includedherein are in particular cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl. One or more double bonds may be present inthis radical.

A (C₆-C₁₈)-aryl radical means an aromatic radical having 6 to 18 Catoms. Radicals included herein are in particular phenyl-, naphthyl-,anthryl- and phenanthryl.

A (C₇-C₁₉)-aralkyl radical means a (C₆-C₁₈)-aryl radical linked via a(C₁-C₈)-alkyl radical to the molecule.

A (C₁-C₁₈)-heteroaryl radical means for the purposes of the invention afive-, six- or seven-membered aromatic ring system having 1 to 18 Catoms and having one or more heteroatoms, preferably N, O or S, in thering. These heteroaryl radicals include for example 1-, 2-, 3-furyl, 1-,2-, 3-pyrrol, 1-, 2-, 3-thienyl, 2-,3-, 4-pyridyl, 2-, 3-, 4-, 5-, 6-,7-indolyl, 3-, 4-, 5-pyrazolyl, 2-, 4-, 5-imidazolyl, 1-, 3-, 4-,5-triazolyl, 1-, 4-, 5-tetrazolyl, acridinyl, quinolinyl,phenanthridinyl, 2-, 4-, 5-, 6-pyrimidinyl and 4-, 5-, 6-,7-(1-aza)-indolizinyl.

A (C₂-C₁₉)-heteroaralkyl radical means a heteroaromatic systemcorresponding to the (C₇-C₁₉)-aralkyl radical.

Halogen or else Hal means in the context of this invention fluorine,chlorine, bromine and iodine.

The amount of polyamino acid employed is not critical and is normally inthe region of 0.001-40 mol %, preferably in the region of 0.01-20 mol %,particularly preferably in the region of 0.01-10 mol %, in each casebased on the α,β-unsaturated enone or α,β-unsaturated sulfone employed.

EXAMPLES

1. Preparation of the Starting Material

L-leucine-NCA: 200.0 g (1.52 mol) of L-leucine were introduced into 2000ml of THF in a standard phosgene apparatus consisting of a 2000 mlfour-necked flask with KPG stirrer. Then 514.28 g (5.2 mol) of phosgenewere passed in at a temperature of 22-33° C. over the course of 6.5 h.The clear reaction solution was then stirred at room temperature for 16h. The solvent was then completely distilled off at 35° C. and 80 mbar.The residue was washed with a total of 1800 ml of n-hexane in portionsand was dried at room temperature under reduced pressure. Yield: 203.2 g(85%)

2. Preparation of the Catalyst

2.1 Inventive Preparation—Variant A

(leu)₁₀-NH—(CH₂)₃—NH-(leu)₁₀(random mixture, average chain lengthindicated): 100.0 g (636.25 mmol) of L-leucine-NCA were introduced into700 ml of anhydrous toluene under argon in a 2 l three-necked flask withfitted reflux condenser (closed with a bubble counter filled withsilicone oil) and mechanical stirrer and subsequently heated to 110° C.Then, at 110° C., 2.358 g (31.81 mmol) of 1,3-diaminopropane in 20 ml ofanhydrous toluene were slowly and cautiously added dropwise to therapidly stirred solution. After the initially very extensive evolutionof gas had subsided, the reaction mixture was stirred at 110° C. for afurther 16 h. The reaction mixture was cooled to room temperature, mixedwith 700 ml of methanol and stirred under reflux. The white solidobtained in this was filtered off at room temperature and stirred asecond time with 1000 ml of methanol under reflux and filtered off. Thepolymer isolated in this way was then dried in a vacuum drying ovenunder reduced pressure (50° C., approx. 15 mbar) overnight. Yield: 67.0g

2.2 Inventive Preparation—Variant B

(leu)₁₀-NH—(CH₂)₃—NH-(leu)₃₃ (random mixture, average chain lengthindicated): 38.0 g of L-leucine-NCA were introduced under argon into a 2l two-necked flask with fitted reflux condenser (closed with a bubblecounter filled with silicone oil) and mechanical stirrer and dissolvedin 970 ml of anhydrous toluene. At room temperature, 0.272 g of1,3-diaminopropane (freshly distilled from CaH₂) in 20 ml of anhydroustoluene were added to the rapidly stirred solution. After the initiallyextensive evolution of gas had subsided, the reaction mixture was slowlyheated to reflux and kept at this temperature for 16 h. The reactionmixture was cooled to room temperature and then centrifuged. The polymerisolated in this way was dried under reduced pressure (50° C.-60° C.,approx. 15 mbar). Finally, the polymer was powdered in a mortar andagain dried over P₂O₅ under reduced pressure. Yield: 25.4 g

2.3 Known Preparation

(cf. Chirality, 1997, 9, 198-202, workup modified)

38 g of L-leucine-NCA were introduced under argon into a 2 l two-neckedflask with fitted reflux condenser (closed with a bubble counter filledwith silicone oil) and magnetic stirrer and dissolved in 970 ml ofanhydrous tetrahydrouran (THF). At room temperature, 0.272 g of1,3-diaminopropane (freshly distilled from CaH₂) in 20 ml of anhydrousTHF were added to the rapidly stirred solution. The reaction mixture wasstirred (approx. 400-500 rpm) at room temperature for 5 days. After thereaction time was complete, workup took place in analogy to theprocedure described under a).Yield: 24.9 g.

3. Catalytic Reactions

General Epoxidation Procedures

The progress of the epoxidations was monitored by HPLC or TLC, withlight being excluded during the epoxidations. Analytical samples werefiltered through a membrane filter before the HPLC measurements.

Example 1

(3-Phase conditions; Chirality, 1997, 9, 198-202, workup modified)

100 mg of pll (not preactivated) were suspended in a mixture of 0.8 mlof toluene, 0.2 ml of NaOH (SM, 4.2 eq.) and 0.2 ml of H₂O₂ (30%, aq.).This mixture was stirred at approx. 1250 rpm for 6 h. Subsequently, 0.24mmol of trans-chalcone and a further 0.5 ml of H₂O₂ (30%, aq.,total=28.5 eq.) were added. After the reaction was complete (or a chosenreaction time), the reaction mixture was diluted with 2 ml of EtOAc andsubsequently centrifuged. The supernatant was then slowly introducedinto a stirred ice-cold aqueous NaHSO₃ solution (4 ml, 20%). After phaseseparation, the organic phase was dried (Na₂SO₄) and concentrated underreduced pressure. Reaction No. Catalyst time (h) Conversion (%) ee (%) 1prepared as in 2.1 1.5 30 87 2 prepared as in 2.2 1.5 59 91 3 preparedas in 2.3 1.5 2 not determined

1. A polyamino acid comprising reacting at least one aminoacid-N-carboxy anhydrides with at least one initiator wherein thereacting of the at least one amino acid-N-carboxy anhydride and the atleast one initiator is carried out under conditions in which a) anaromatic solvent is used; b) the reaction temperature is between 30° C.and the boiling point of the reaction mixture, and c) the molar ratio ofamino acid-NCA to the initiator is between 4:1 and 200:1.
 2. A methodfor producing polyamino acids comprising reacting amino acid-N-carboxyanhydrides with an initiator wherein the reacting of the at least oneamino acid-N-carboxy anhydride and the at least one initiator is carriedout under conditions in which a) an aromatic solvent is used; b) thereaction temperature is between 30° C. and the boiling point of thereaction mixture, and c) the molar ratio of amino acid-NCA to theinitiator is between 4:1 and 200:1.
 3. An process comprising convertinga C—C double bond of compound into an oxirine, wherein the process is anepoxidation reaction carried out with a polyamino acid catalyst; whereinthe polyamino acid catalyst is made by a process involving reacting atleast one amino acid-N-carboxy anhydride with at least one initiatorwherein the reacting of the at least one amino acid-N-carboxy anhydrideand the at least one initiator is carried out under conditions in whicha) an aromatic solvent is used: b) the reaction temperature is between30° C. and the boiling point of the reaction mixture, and c) the molarratio of amino acid-NCA to the initiator is between 4:1 and 200:1. 4.The process of claim 3, wherein the C—C double bond is a C—C double bondof a compound selected from the group consisting of α,β-unsaturatedenones, α,β-unsaturated sulfones.
 5. The process of claim 4, wherein the,β-unsaturated enones or α,β-unsaturated sulfones the compounds of thegeneral formula (II)

in which X is (C═O) or (SO₂), and R⁵ and R⁶ are identical or differentand are (C₁-C₁₈)-alkyl, (C₂-C₁₈)-alkenyl, (C₂-C₁₈)-alkynyl,(C₃-C₈)-cycloalkyl, (C₆-C₁₈)-aryl, (C₇-C₁₉)-aralkyl, (C₁-C₁₈)heteroarylor (C₂-C₁₉)-heteroaralkyl, wherein the radicals mentioned for R⁵ andR⁶may be substituted once or more than once by identical or differentradicals R⁷, halogen, NO₂, NR⁷ R⁸, PO₀₋₃R⁷R⁸, SO₀₋₃R⁷, OR⁷, CO₂R⁷,CONHR⁷ or COR⁷, and optinoally one or more CH₂ groups in the radicals R⁵and R⁶ are substituted by O, SO₀₋₂, NR⁷ or PO₀₋₂R⁷, wherein R⁷ and R⁸are identical or different and are H, (C₁-C₁₈)-alkyl, (C₂-C₁₈)-alkenyl,(C₂-C₁₈)-alkynyl, (C₃-C₈)-cycloalkyl, (C₆-C₁₈)-aryl,(C₁-C₁₈)-heteroaryl, (C₁-C₈)-alkyl-(C₆-C₈)-aryl,(C₁-C₈)-alkyl-(C₁-C₁₉)-heteroaryl, (C₁-C₈)-alkyl-(C₃-C₈)-cyocloalkyl,and these radicals R⁷ and R⁸ may be substituted once or more than onceby identical or different halogen radicals.